WO2014168139A1 - Procédé de fabrication d'acide 3,4,5-tricaféoylquinique - Google Patents

Procédé de fabrication d'acide 3,4,5-tricaféoylquinique Download PDF

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WO2014168139A1
WO2014168139A1 PCT/JP2014/060176 JP2014060176W WO2014168139A1 WO 2014168139 A1 WO2014168139 A1 WO 2014168139A1 JP 2014060176 W JP2014060176 W JP 2014060176W WO 2014168139 A1 WO2014168139 A1 WO 2014168139A1
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group
formula
compound represented
optionally substituted
acid
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幸蔵 佐藤
寛之 内藤
邑上　健
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富士フイルム株式会社
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Priority to DE112014001871.6T priority Critical patent/DE112014001871B4/de
Priority to JP2015511264A priority patent/JP6139667B2/ja
Priority to CN201480020134.8A priority patent/CN105143171B/zh
Publication of WO2014168139A1 publication Critical patent/WO2014168139A1/fr
Priority to US14/876,931 priority patent/US9475752B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a method for producing 3,4,5-tricaffeoylquinic acid.
  • Non-patent Document 1 Chlorogenic acids, a kind of polyphenol, are contained in coffee beans, sweet potato leaves, mugwort, watermelon or sunflower, and have been extracted from plants using hot water or ethanol. However, it has been extremely difficult to purify chlorogenic acids to such an extent that they can be used as pharmaceuticals.
  • 3,4,5-tricaffeoylquinic acid has the highest physiological activity among chlorogenic acids, and has various physiological activities such as strong antitumor action, antidiabetic action, antihypertensive action and antiviral action (Non-Patent Document 2).
  • 3,4,5-tricaffeoylquinic acid is obtained by extracting from sweet potato stems and leaves or Brazilian propolis with alcohol, defatted with hexane, and fractionated by adsorption chromatography and gel filtration chromatography (patented) Reference 1).
  • Non-Patent Document 3 has a long process, complicated operation, requires expensive reagents, requires extremely low temperature reaction conditions, and is extremely long in removing the protecting group in the final process. It had various problems such as taking time.
  • the present invention is capable of producing 3,4,5-tricaffeoylquinic acid efficiently by a simple operation in a short process using an inexpensive raw material. It aims at providing the manufacturing method of a quinic acid.
  • Step (1) in which a compound represented by Formula (1) described later or a compound represented by Formula (2) described below is reacted with a compound represented by Formula (4) described later, And deprotecting the product obtained in 1) to produce 3,4,5-tricaffeoylquinic acid represented by formula (6) to be described later, A method for producing 5-tricaffeoylquinic acid.
  • (2) The production method according to (1), wherein the step (1) is performed in a solvent having an SP value of 8.0 to 10.0.
  • (3) The production method according to (1) or (2), wherein the reaction temperature in the step (1) is ⁇ 10 ° C. to 30 ° C.
  • step (1) a compound represented by formula (1a) described later is used, and before step (1), a compound represented by formula (A3) described later and formula (A5) described later are used.
  • the production method according to any one of (1) to (3) comprising a step (3) of reacting a compound represented by formula (1a) to obtain a compound represented by formula (1a) described later.
  • X 1 is a halogen atom.
  • step (2) The production method according to any one of (1) to (5), wherein X 1 is a chlorine atom.
  • R 1 is a hydroxyl protecting group and R 2 is a carboxyl protecting group.
  • R 1 is an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, or an optionally substituted acyl group, The production method according to any one of (1) to (7), wherein R 2 is an optionally substituted C 1-6 alkyl group or an optionally substituted C 2-6 alkenyl group.
  • R 1 is a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom
  • R 2 is a C 1-6 alkyl group which may be substituted with a halogen atom.
  • R 6 and R 7 are the same or different and each represents an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, or an optionally substituted acyl group.
  • (1) The production method according to any one of (9).
  • (11) The production method according to any one of (1) to (10), wherein R 6 and R 7 are the same or different and are a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom. .
  • (12) The production method according to any one of (1) to (11), wherein R 3 , R 4 and R 5 are hydrogen atoms.
  • R 1a represents an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, or an optionally substituted acyl group, The compound or a salt thereof according to (13), wherein R 2a represents an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2-6 alkenyl group.
  • R 1a represents a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom
  • R 6 and R 7 are the same or different and each represents an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, or an optionally substituted acyl group; (13) The compound or a salt thereof according to any one of (15). (17) The compound according to any one of (13) to (16), wherein R 6 and R 7 are the same or different and each represents a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom, Its salt. (18) The compound or a salt thereof according to any one of (13) to (17), wherein R 3 , R 4 and R 5 are hydrogen atoms.
  • the present invention it is possible to provide a production method capable of producing 3,4,5-tricaffeoylquinic acid efficiently in a large amount and with high purity by a simple operation in a short process using an inexpensive raw material. it can.
  • FIG. 1B is a 1 H-NMR spectrum synthesized in Synthesis Example 2.
  • 2 is a 1D 1 H-NMR spectrum synthesized in Synthesis Example 4.
  • FIG. 1 is a 1 H-NMR spectrum of 1E synthesized in Synthesis Example 5.
  • 2 is a 1 H-NMR spectrum of methyl 1 -carbomethoxy-3,4-O-isopropylidene-5- (3,4-dicarbomethoxycaffeoyl) quinate synthesized in Synthesis Example 9.
  • FIG. 9 is a 1 H-NMR spectrum of methyl 1 -carbomethoxy-3,4-O-isopropylidene-5- (3,4-dicarbomethoxycaffeoyl) quinate synthesized in Synthesis Example 9.
  • FIG. 2 is a 1 H-NMR spectrum of 1 -carbomethoxy-3,4-bis- (3,4-dicarbomethoxycaffeoyl) -1,5-quinidelactone synthesized in Synthesis Example 10.
  • FIG. 2 is a 1 H-NMR spectrum of methyl 1-carbomethoxy-3,4,5-tris (3,4-dicarbomethoxycaffeoyl) quinate synthesized in Synthesis Example 11.
  • FIG. 2 is a 1 H-NMR spectrum of 3,4,5-tricaffeoylquinic acid synthesized in Synthesis Example 11.
  • 2 is a 1 H-NMR spectrum of 3,4,5-tris (3,4-dicarbomethoxycaffeoyl) quinic acid synthesized in Synthesis Example 12.
  • FIG. 2 is a 1 H-NMR spectrum of methyl 1-carbomethoxy-3,4,5-tris (3,4-diallylic caffeoyl) quinate synthesized in Synthesis Example 28.
  • FIG. 2 is a 1 H-NMR spectrum of 3,4,5-tris (3,4-diallylic caffeoyl) quinic acid synthesized in Synthesis Example 28.
  • FIG. 2 is a 1 H-NMR spectrum of 3,4,5-tris (3,4-diallylic caffeoyl) quinic acid synthesized in Synthesis Example 28.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the C 1-6 alkyl group is a linear or branched C 1-6 carbon atom such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl groups.
  • the C 2-6 alkenyl group is a linear or branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups.
  • the C 2-6 alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.
  • the C 3-8 cycloalkyl group means a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • An aryl group means a phenyl or naphthyl group.
  • An al C 1-6 alkyl group means an al C 1-6 alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl and naphthylmethyl groups.
  • the C 1-6 alkoxy group is a linear or branched carbon number of 1 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
  • An aryloxy group means a phenoxy or naphthyloxy group.
  • the C 1-6 alkoxy C 1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms substituted by alkyloxy having 1 to 6 carbon atoms such as methoxymethyl and 1-ethoxyethyl groups.
  • the C 2-6 alkanoyl group means a linear or branched alkanoyl group having 2 to 6 carbon atoms such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
  • An aroyl group means a benzoyl or naphthoyl group.
  • An acyl group means a formyl group, a C 2-6 alkanoyl group or an aroyl group.
  • the C 2-6 alkanoyloxy group means a linear or branched alkanoyloxy group having 2 to 6 carbon atoms such as acetyloxy and propionyloxy groups.
  • An aroyloxy group means a benzoyloxy group or a naphthoyloxy group.
  • the acyloxy group means a C 2-6 alkanoyloxy group or an aroyloxy group.
  • the C 1-6 alkoxycarbonyl group is a linear or branched C 1-6 carbon atom such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl group.
  • An aryloxycarbonyl group means a phenyloxycarbonyl or naphthyloxycarbonyl group.
  • the C 1-6 alkylsulfonyl group means an alkylsulfonyl group having 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
  • An arylsulfonyl group means a benzenesulfonyl or naphthalenesulfonyl group.
  • the C 1-6 alkylsulfonyloxy group means an alkylsulfonyloxy group having 1 to 6 carbon atoms such as methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy groups.
  • the arylsulfonyloxy group means benzenesulfonyloxy or naphthalenesulfonyloxy group.
  • a C 1-3 alkylene group means a methylene, ethylene or propylene group.
  • a silyl group means a trimethylsilyl, triethylsilyl, or tributylsilyl group.
  • the di (C 1-6 alkyl) phosphoryl group, dimethylphosphoryl means di (C 1-6 alkyl) phosphoryl group such as diethyl phosphite Hollis and dibutyl phosphoryl group.
  • the diarylphosphoryl group means a diphenylphosphoryl group and the like.
  • the diarylphosphinyl group means a diphenylphosphinyl group and the like.
  • the leaving group means a halogen atom, a C 1-6 alkylsulfonyloxy group, an arylsulfonyloxy group, or the like. These groups may be substituted with one or more groups selected from the substituent group A described later.
  • Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons , INC.).
  • al C 1-6 alkyl group a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, a C 1-6 alkylsulfonyl group, an aryl A sulfonyl group, a silyl group, etc. are mentioned. These groups may be substituted with one or more groups selected from the substituent group A.
  • the carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis 4th Edition, 533-646, 2007, John Wiley & Sons , INC.). Specific examples include a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl group, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, a silyl group, and the like. These groups may be substituted with one or more groups selected from the substituent group A described later.
  • Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-366, 2007, John Wiley & Sons , INC.). Specific examples include a C 1-6 alkyl group, a C 2-6 alkenyl group, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, Aryloxycarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, di (C 1-6 alkyl) phosphoryl group, diarylphosphoryl group, diarylphosphinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, silyl group, etc. Is mentioned. These groups may be substituted with one or more groups selected from the substituent group A described later.
  • the phenolic hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary phenolic hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 370-424, 2007, John Wiley & Sons, INC.). Specific examples include a C 1-6 alkyl group, a C 2-6 alkenyl group, an al C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an acyl group, a C 1-6 alkylsulfonyl group, An arylsulfonyl group or a silyl group is mentioned. These groups may be substituted with one or more groups selected from the substituent group A.
  • Substituent group A one or more selected from a halogen atom, a cyano group, a nitro group, an amino group that may be protected, a hydroxyl group that may be protected, a carboxyl group that may be protected, and a substituent group B described later
  • Substituent group B halogen atom, cyano group, nitro group, amino group which may be protected, hydroxyl group which may be protected, carboxyl group which may be protected, C 1-6 alkyl group, aryl group, C 1 -6 alkoxy group, oxo group.
  • Examples of the aliphatic hydrocarbons include pentane, hexane, cyclohexane, heptane, and petroleum ether.
  • Examples of halogenated hydrocarbons include methylene chloride, chloroform or 1,2-dichloroethane.
  • Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
  • Examples of ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether.
  • esters examples include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.
  • ketones examples include acetone, 2-butanone and 4-methyl-2-pentanone.
  • amides examples include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone.
  • Secondary amines include dimethylamine, diethylamine, dipropylamine, dibutylamine, pyrrolidine, piperidine, piperazine or morpholine.
  • the C 1-6 alkyl group, aryl group or C 1-6 alkoxy group of R a may be substituted with one or more groups selected from the substituent group A.
  • the C 1-6 alkoxycarbonyl group, aryloxycarbonyl group or acyl group of R 1 may be substituted with one or more groups selected from the substituent group A.
  • the ar C 1-6 alkyl group, C 2-6 alkanoyl group, aroyl group, C 1-6 alkoxycarbonyl group, aryloxycarbonyl group, C 1-6 alkylsulfonyl group or arylsulfonyl group of R 1a is a substituent group. It may be substituted with one or more groups selected from A.
  • the C 1-6 alkyl group or C 2-6 alkenyl group of R 2 may be substituted with one or more groups selected from Substituent Group A.
  • the C 1-6 alkyl group, C 2-6 alkenyl group, aryl group or al C 1-6 alkyl group of R 2a may be substituted with one or more groups selected from Substituent Group A.
  • the C 1-6 alkoxycarbonyl group, aryloxycarbonyl group or acyl group of R 6 may be substituted with one or more groups selected from the substituent group A.
  • the C 1-6 alkoxycarbonyl group, aryloxycarbonyl group or acyl group of R 7 may be substituted with one or more groups selected from the substituent group A.
  • the methylene group formed by R 6 and R 7 together may be substituted with one or more groups selected from the substituent group A.
  • Examples of the salt of the compound represented by the formula (1-1) include generally known salts of basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
  • salts in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
  • alkali metals such as sodium and potassium
  • alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine,
  • a compound represented by formula (1) described later or a compound represented by formula (2) described later is used as a starting material.
  • at least one hydroxyl group in the groups represented by OR 3 , OR 4 , and OR 5 contained in these compounds, and the X 1 group in the compound represented by the formula (4) described later To form an ester bond, and then remove (eliminate) a protecting group contained in the product (for example, hydroxyl protecting group, carboxyl protecting group, phenolic hydroxyl protecting group, etc.) 3,4,5-tricaffeoylquinic acid can be easily produced.
  • a protecting group contained in the product for example, hydroxyl protecting group, carboxyl protecting group, phenolic hydroxyl protecting group, etc.
  • the first embodiment of the production method of the present invention is the step (A1) in which the compound represented by the formula (1) and the compound represented by the formula (4) are reacted, and the product obtained in the step (A1). And a step (A2) of producing 3,4,5-tricaffeoylquinic acid by performing a deprotection reaction to remove the protecting group from
  • a step (A2) of producing 3,4,5-tricaffeoylquinic acid by performing a deprotection reaction to remove the protecting group from
  • step (A1) in step (A1), as shown in the following scheme, a compound represented by formula (5-1) is reacted with a compound represented by formula (4) to obtain a compound represented by formula (5-1) It is. First, the compound used at this process is explained in full detail.
  • R 1 and R 2 are such that R 1 represents a hydrogen atom or a hydroxyl protecting group, R 2 represents a hydrogen atom or a carboxyl protecting group, and at least one of R 1 and R 2 is not a hydrogen atom, or , R 1 and R 2 together represent a protecting group represented by —B (R a ) —.
  • the definition (meaning) of R 1 and R 2 is the following (A) or (B).
  • R 2 represents a hydrogen atom or a carboxyl protecting group
  • at least one of R 1 and R 2 is not a hydrogen atom.
  • R 1 and R 2 together represent a protecting group represented by —B (R a ) —.
  • Specific embodiments of the above (A) include embodiments X in which R 1 is a hydroxyl protecting group and R 2 is a carboxyl protecting group, R 1 is a hydrogen atom, and R 2 is a carboxyl protecting group. And embodiment Z in which R 1 is a hydroxyl protecting group and R 2 is a hydrogen atom.
  • embodiment X is preferred in that 3,4,5-tricaffeoylquinic acid can be produced more efficiently.
  • at least one of R 3 , R 4 and R 5 represents a hydrogen atom.
  • R 1 is a hydrogen atom
  • the compound represented by the formula (4) is: The reaction proceeds preferentially with an OH group in which at least one of R 3 , R 4 and R 5 is a hydrogen atom rather than an OH group in which R 1 is a hydrogen atom. Details of the reason is unknown, because of the R 2 COO- hindered adjacent to R 1 O-, the compounds represented by formula (4) is unlikely to proceed reaction with R 1 O- Guessed.
  • R 1 may be a C 1-6 alkoxycarbonyl group that may be substituted, an aryloxycarbonyl group that may be substituted, or a substituent that may be substituted.
  • a good acyl group is preferable, and a C 1-6 alkoxycarbonyl group which may be substituted with one or more groups selected from the substituent group A may be substituted with one or more groups selected from the substituent group A.
  • aryloxycarbonyl group or, one or more more preferably an acyl group which may be substituted with a group, a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom selected from the substituent group a
  • a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom selected from the substituent group a
  • the al, methoxycarbonyl group or trichloroethoxycarbonyl group is most preferred.
  • R 2 is preferably a C 1-6 alkyl group which may be substituted or a C 2-6 alkenyl group which may be substituted, so that the effect of the present invention is more excellent. More preferably a C 1-6 alkyl group which may be substituted with one or more groups selected from the above, or a C 2-6 alkenyl group which may be substituted with one or more groups selected from substituent group A. An optionally substituted C 1-6 alkyl group is more preferred, and a methyl group or trichloroethyl group is most preferred.
  • the compound represented by the formula (5-1) can be deprotected more efficiently under the condition that the caffeoyl group is not cleaved. can do.
  • R 1 is a C 1-6 alkoxycarbonyl group
  • R 2 is a C 1-6 alkyl group.
  • R 1 is a C 1-6 alkoxycarbonyl group substituted with a halogen atom
  • R 2 is preferably a C 1-6 alkyl group substituted with a halogen atom.
  • R a represents an optionally substituted C 1-6 alkyl group, an optionally substituted aryl group or an optionally substituted C 1-6 alkoxy group.
  • R a is preferably an optionally substituted aryl group or an optionally substituted C 1-6 alkoxy group, more preferably an optionally substituted aryl group.
  • a phenyl group is more preferable. More specifically, when R 1 and R 2 together represent —B (R a ) —, the compound represented by the formula (1) is represented by the following structural formula.
  • R 3 , R 4 and R 5 are the same or different and each represents a hydrogen atom or a group represented by the formula (3). Note that at least one of R 3 , R 4 and R 5 represents a hydrogen atom. Among these, it is preferable that at least two of R 3 , R 4 and R 5 are hydrogen atoms in that 3,4,5-tricaffeoylquinic acid can be efficiently produced with fewer steps, and all of them are hydrogen. More preferably it is an atom.
  • R 6 and R 7 are the same or different and represent a phenolic hydroxyl protecting group, or R 6 and R 7 together represent a carbonyl group (—CO—) and a substituent. And represents a protecting group selected from the group consisting of methylene groups. * Indicates a bonding position with the oxygen atom of the compound represented by the formula (1).
  • R 6 is an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted C 2-6 alkenyl group, or the like, in that the effects of the present invention are more excellent.
  • An acyl group which may be substituted is preferable, a C 1-6 alkoxycarbonyl group which may be substituted with one or more groups selected from substituent group A, and a substituent which is substituted with one or more groups selected from substituent group A
  • An aryloxycarbonyl group which may be substituted, a C 2-6 alkenyl group which may be substituted with one or more groups selected from Substituent Group A or one or more groups selected from Substituent Group A more preferably also an acyl group, more preferably a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom, a methoxycarbonyl group or trichloroethoxycarbonyl group is most preferred.
  • the compound represented by formula (5-1) can be removed more efficiently under the condition that the caffeoyl group is not cleaved. Can be protected.
  • an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted C 2-6 alkenyl group or An acyl group which may be substituted is preferable, a C 1-6 alkoxycarbonyl group which may be substituted with one or more groups selected from substituent group A, and a substituent which is substituted with one or more groups selected from substituent group A
  • An aryloxycarbonyl group which may be substituted, a C 2-6 alkenyl group which may be substituted with one or more groups selected from Substituent Group A or one or more groups selected from Substituent Group A more preferably also an acyl group, more preferably a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom, a methoxycarbonyl group or trichloroethoxycarbonyl group is most preferred.
  • R 7 By using a C 1-6 alkoxycarbonyl group which may be substituted with a halogen atom as R 7 , the compound represented by the formula (5-1) can be removed more efficiently under the condition that the caffeoyl group is not cleaved. Can be protected. Further, it is preferred R 6 and R 7 are the same.
  • X 1 represents a hydroxyl group or a leaving group.
  • the type of the leaving group is not particularly limited, but X 1 is preferably a halogen atom, more preferably a chlorine atom, in that the reaction proceeds more efficiently.
  • R 6 and R 7 are as described above.
  • the procedure of this step is not particularly limited as long as the product represented by the above formula (5-1) can be obtained, but it can be roughly divided into two methods depending on the type of X 1 in the formula (4). Hereinafter, each method (method M1 and method M2) will be described in detail.
  • Method M1 Method using a compound represented by the formula (4) in which X 1 is a hydroxyl group
  • X 1 in the formula (4) is a hydroxyl group
  • the compound represented by the formula (1) is reacted with the compound represented by the formula (4) by using a condensing agent, and the formula (5-1) The compound represented by these can be manufactured.
  • a known condensing agent can be used.
  • (O)-(7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetra Methyluronium hexafluorophosphate 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole, 2-chloro-1-methylpyridinium iodide, 4- (4,6- And dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine chloride and ((benzotriazol-1-yl) oxy) (trispyrrolidino) phosphonium hexafluorophosphate.
  • the amount of the condensing agent used is appropriately selected depending on the structure of the compound represented by the formula (1) used.
  • the amount of the condensing agent used is preferably 3 to 30 times the moles of the compound represented by the formula (1), and 3.3 to 9.0 times mole is more preferable.
  • the amount of the condensing agent used is preferably 2 to 20 times the mol of the compound represented by the formula (1).
  • the molar ratio is more preferably 6.0 times mole.
  • the amount of the condensing agent used is preferably 1 to 10 moles compared to the compound represented by the formula (1), 1.1 A molar ratio of ⁇ 3.0 times is more preferable.
  • the reaction may be performed in the presence of a base as necessary. Due to the presence of the base, the reaction proceeds more efficiently and the yield is improved.
  • the type of base used is not particularly limited.
  • pyridines such as pyridine, picoline, lutidine, collidine and 4-dimethylaminopyridine
  • diamines such as tetramethylethylenediamine
  • trialkylamines such as triethylamine and diisopropylethylamine 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonene (DBN) and 1,4-diazabicyclo [2.2 .2]
  • DBU 1,8-diazabicyclo [4.3.0] -5-nonene
  • DBN 1,5-diazabicyclo [2.2 .2]
  • Polycycloamines such as octane (DABCO) are mentioned, pyr
  • the amount of the base used is appropriately selected depending on the structure of the compound represented by the formula (1) used.
  • the amount of the base used is preferably 3 to 30 times by mole with respect to the compound represented by formula (1), and 3.3 to 9. 0 times mole is more preferable.
  • the amount of the base used is preferably 2 to 20 times the moles of the compound represented by the formula (1), 2.2 to 6.0 moles are more preferred.
  • the amount of the base used is preferably 1 to 10 moles compared to the compound represented by the formula (1), 1.1 to 3.0 times mole is more preferable.
  • a solvent may be used as necessary.
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, nitriles And esters, and these solvents may be used as a mixture.
  • a solvent other than the above may be mixed as long as it does not affect the reaction.
  • Preferred solvents include halogenated hydrocarbons and nitriles, with methylene chloride, acetonitrile and propanenitrile being more preferred.
  • the amount of the solvent used is not particularly limited, but it is preferably 1 to 50 times (v / w), more preferably 1 to 15 times (v / w) based on the compound represented by formula (1).
  • a solvent having an SP value of 8.0 to 10.0 because the reaction proceeds more efficiently and the yield is improved.
  • the SP value is a solubility parameter and is a characteristic value that is a measure of the mixing property between liquids.
  • a value calculated by the Fedors method can be used. Examples thereof include a solvent having an SP value of 8.0 to 10.0 selected from aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones and esters.
  • butyl acetate SP value: 8.5
  • xylene SP value: 8.8
  • toluene SP value: 8.8
  • ethyl acetate SP value: 9.0
  • benzene SP value: 9.2
  • dibutyl Examples include phthalate (SP value: 9.4) and methylene chloride (SP value: 9.7).
  • the amount of the compound represented by formula (4) is appropriately selected depending on the structure of the compound represented by formula (1) used. For example, when R 3 , R 4 and R 5 are all hydrogen atoms, the amount of the compound represented by formula (4) is 3.0 to 7.7 with respect to the compound represented by formula (1). 5-fold moles are preferred, and 3.3-4.5 moles are more preferred. Further, when two of R 3 , R 4 and R 5 are hydrogen atoms, the amount of the compound represented by the formula (4) is 2.0 to 2.0% relative to the compound represented by the formula (1). 5.0 times mole is preferable, and 2.2 to 3.0 times mole is more preferable.
  • the amount of the compound represented by the formula (4) is 1.0 to 1.0% relative to the compound represented by the formula (1). 2.5 moles are preferred, and 1.1 to 1.5 moles are more preferred.
  • the reaction conditions for Method M1 are not particularly limited, and optimum conditions are selected depending on the compounds used.
  • the reaction temperature is preferably ⁇ 10 ° C. to 50 ° C., more preferably 0 ° C. to 40 ° C., from the viewpoint that the reaction proceeds more efficiently.
  • the reaction time is preferably 20 minutes to 8 hours, more preferably 30 minutes to 4 hours, from the viewpoint of product yield and productivity.
  • the compound represented by the formula (4) is reacted with an acid halide or an acid anhydride to convert to a mixed acid anhydride, and then in the presence of a base, the formula (1)
  • the compound represented by the formula (5-1) can also be produced by reacting the compound represented by the formula (4) with the compound represented by the formula (4).
  • the acid halide or acid anhydride used in this reaction include chloroformates such as methyl chloroformate, ethyl chloroformate and trichloroethyl chloroformate, and acid anhydrides such as trifluoroacetic anhydride.
  • the compound represented by the formula (5-1) can also be produced by reacting the compound represented by the formula (1) with the compound represented by the formula (4) in the presence of a base.
  • the sulfonic acid halide used in the mixed acid anhydride with sulfonic acid include methanesulfonyl chloride, benzenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride.
  • Preferred reaction conditions for reacting these mixed acid anhydrides with the compound represented by the formula (1) are the same as those applied to the method M1.
  • Method M2 Method using a compound represented by formula (4) wherein X 1 is a halogen atom
  • X 1 in the formula (4) is a halogen atom
  • the compound represented by the formula (1) is reacted with the compound represented by the formula (4) in the presence of a base to obtain a formula (5-1)
  • the compounds represented can be produced.
  • This reaction corresponds to a reaction between a so-called carboxylic acid halide and an alcohol.
  • the compound represented by the formula (4) in which X 1 is a halogen atom can be produced by reacting the compound represented by the formula (4) in which X 1 is a hydroxyl group with a halogenating agent.
  • halogenating agent to be used known compounds can be used, and examples thereof include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride and phosphorus pentachloride.
  • the type of base used in Method M2 is not particularly limited, and examples include the bases described in Method M1 above.
  • the amount of the base used is appropriately selected depending on the structure of the compound represented by the formula (1) to be used, and examples include the amount used in the above method M1.
  • a solvent may be used as necessary.
  • the kind in particular of solvent used is not restrict
  • the amount used is also as described above.
  • the amount of the compound represented by the formula (4) is appropriately selected depending on the structure of the compound represented by the formula (1) to be used. Amount etc.
  • the reaction conditions for Method M2 are not particularly limited, and optimum conditions are selected depending on the compounds used.
  • the reaction temperature is preferably ⁇ 20 ° C. to 40 ° C., more preferably ⁇ 10 ° C. to 30 ° C., from the viewpoint that the reaction proceeds more efficiently.
  • the reaction time is preferably 20 minutes to 8 hours, more preferably 30 minutes to 4 hours, from the viewpoint of product yield and productivity.
  • the product and impurities may be separated and purified as necessary.
  • Separation and purification may be performed by a conventional method, and examples include extraction operation using an organic solvent, recrystallization, crystallization using a poor solvent, and column chromatography using silica gel. In the present specification, the above process is hereinafter simply referred to as “separation and purification process”.
  • step (A2) the product (compound represented by formula (5-1)) obtained in step (A1) is deprotected, and 3,4,5-tricaffeoyl oil is obtained. It is a process for producing quinic acid. More specifically, the protecting group (hydroxyl protecting group, carboxyl protecting group, phenolic hydroxyl protecting group, -B (R a )-, etc.) contained in the compound represented by the above formula (5-1) is removed. This is a step of releasing (removing) to obtain a desired 3,4,5-tricaffeoylquinic acid. In this step, deprotection is intended to remove the group protecting the hydroxyl group, phenolic hydroxyl group and carboxyl group in 3,4,5-tricaffeoylquinic acid as described above. .
  • the compound represented by the formula (6) can be produced by deprotecting the compound represented by the formula (5-1). This reaction is described, for example, in Protective Groups in Organic Synthesis 4th edition, pages 367-430, 2007, John Wiley & Sons, INC. .)).
  • a method using a nucleophile (method M3) or a method using zinc dust (method M4) can be mentioned. Hereinafter, each method will be described in detail.
  • the compound represented by the formula (6) can be produced by reacting the compound represented by the formula (5-1) with a nucleophile.
  • the type of nucleophile used in this reaction is not particularly limited, but for example, lithium chloride, lithium bromide, lithium iodide, trimethylsilyl iodide, trimethylsilyl chloride / sodium iodide, sodium iodide, sodium dodecylthiolate, sodium Hexadecyl thiolate, and disodium thioglycolate, including lithium chloride, lithium chloride / sodium bromide, lithium chloride / potassium bromide, lithium chloride / sodium iodide, lithium chloride / potassium iodide, lithium bromide and Lithium iodide is preferred, and lithium chloride / sodium bromide, lithium chloride / sodium iodide, lithium bromide and lithium iodide are more preferred, and lithium chloride / sodium bromide, lithium chlor
  • a solvent may be used as necessary.
  • the solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include nitriles, amides and pyridines, and these solvents may be used as a mixture.
  • Preferred solvents include acetonitrile, propanenitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylimidazolidinone, picoline, lutidine and collidine.
  • the amount of the solvent used is not particularly limited, but it is preferably 2 to 50 times (v / w), more preferably 3 to 20 times (v / w) with respect to the compound represented by formula (5-1). preferable.
  • An acid may be added to this reaction as necessary. By adding an acid, side reactions can be reduced and the yield can be improved.
  • the amount of the acid used is preferably 1 to 10 times by mole, more preferably 3 to 6 times by mole, relative to the compound represented by the formula (5-1) from the viewpoint that it does not adversely affect the deprotection reaction.
  • the type of acid is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrogen chloride, hydrogen bromide, and hydrogen iodide. When a basic solvent such as pyridine is used, it can be added as a salt thereof.
  • the reaction conditions in Method M3 are not particularly limited, and optimum conditions are selected according to the compound used.
  • the reaction temperature is preferably 20 to 180 ° C., more preferably 60 to 150 ° C., in that the reaction proceeds more efficiently.
  • the reaction time is preferably 10 minutes to 12 hours, more preferably 30 minutes to 5 hours from the viewpoint of product yield and productivity.
  • the compound represented by formula (6) can be produced by reacting the compound represented by formula (5-1) with zinc dust.
  • a solvent may be used as necessary.
  • the solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include the solvents described in the above method M1, and formic acid, acetic acid and propionic acid are preferable.
  • the amount of the solvent used is not particularly limited, but it is preferably 3 to 50 times (v / w), more preferably 4 to 30 times (v / w) with respect to the compound represented by formula (5-1). preferable.
  • the amount of zinc powder used in this reaction is not particularly limited, but is preferably 10 to 60 times mol, more preferably 12 to 30 times mol for the compound represented by formula (5-1).
  • the reaction conditions in Method M3 are not particularly limited, and optimal conditions are selected according to the compounds used.
  • the reaction temperature is preferably 10 to 100 ° C., more preferably 20 to 50 ° C., in that the reaction proceeds more efficiently.
  • the reaction time is preferably 10 minutes to 12 hours, more preferably 30 minutes to 3 hours, from the viewpoint of product yield and productivity.
  • R 1 , R 6 and R 7 contain an alkenyl group
  • a method in which deprotection is performed using a palladium catalyst is also included.
  • the palladium catalyst is not particularly limited, and examples thereof include palladium acetate, tetrakistriphenylphosphine palladium, dichloroditriphenylphosphine palladium and Pd—C. Palladium acetate and tetrakistriphenylphosphine palladium are preferred, and tetrakistriphenylphosphine palladium is preferred. More preferred.
  • the amount of the palladium catalyst used is preferably 0.001 to 2 moles, more preferably 0.02 to 0.5 moles, relative to the compound represented by Formula (5-1). Moreover, in this method, it is preferable that a nucleophilic species that reacts with allyl palladium exists.
  • the nucleophilic species include water, alcohols and secondary amines.
  • water, methanol, morpholine, diethylamine and pipediline are preferable, and morpholine is more preferable.
  • the amount of the nucleophilic species to be used is not particularly limited, but is preferably 2 to 100 times mol, more preferably 10 to 60 times mol for the compound represented by the formula (5-1).
  • the reaction conditions in this method are not particularly limited, and optimum conditions are selected according to the compound used.
  • the reaction temperature is preferably 20 to 180 ° C., more preferably 10 to 50 ° C., in that the reaction proceeds more efficiently.
  • the reaction time is preferably 10 minutes to 12 hours, more preferably 30 minutes to 5 hours from the viewpoint of product yield and productivity.
  • the compound represented by the formula (5-1) may be contacted with an acidic aqueous solution to remove -B (R a )-.
  • an acidic aqueous solution examples include phosphoric acid, hydrochloric acid, and sulfuric acid.
  • the temperature of the acidic aqueous solution is not particularly limited, but is preferably 0 ° C. to 40 ° C., more preferably 0 ° C. to 30 ° C. in terms of more efficient reaction.
  • the reaction time of the compound represented by the formula (5-1) and the acidic aqueous solution is not particularly limited, but is preferably 1 to 30 minutes from the viewpoint of the yield and productivity of the product, and 3 to 10 minutes. More preferred. Note that the treatment of desorbing —B (R a ) — may be performed after the method M3 or the method M4 is performed.
  • the deprotection procedure may be performed step by step. More specifically, the portion represented by R 6 and R 7 may be deprotected in the first stage, and the portion represented by R 1 and R 2 may be deprotected in the second stage. .
  • a deprotection method a known method including the above-described method can be adopted.
  • a deprotection method in the first step for example, a method using a strong base such as lithium hydroxide or hydrazine can be employed.
  • a product and impurities may be separated and purified as necessary.
  • the desired 3,4,5-tricaffeoylquinic acid can be efficiently produced through the steps (A1) and (A2).
  • 3,4,5-tricaffeoylquinic acid can be used in various applications, for example, various physiology such as antitumor action, antidiabetic action, antihypertensive action, antiviral action and whitening effect, bactericidal effect, etc. Since it has activity, various pharmaceuticals and quasi drugs, foods for specific insurance, health supplements, cosmetics, and the like can be mentioned.
  • a preferred embodiment of the compound represented by the above formula (1) includes a compound represented by the formula (1-1) or a salt thereof.
  • R 1a represents an optionally substituted al C 1-6 alkyl group, a formyl group, an optionally substituted C 2-6 alkanoyl group, an optionally substituted aroyl group, a substituted An optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted aryloxycarbonyl group, an optionally substituted C 1-6 alkylsulfonyl group, or an optionally substituted arylsulfonyl group is shown.
  • R 2a is an optionally substituted C 1-6 alkyl group, substituted by optionally C 2-6 alkenyl group, an optionally substituted aryl group, or, optionally substituted aralkyl C 1-6 alkyl group Indicates.
  • the definitions of R 3 , R 4 and R 5 are as described above.
  • R 1a is preferably a C 1-6 alkoxycarbonyl group which may be substituted, an aryloxycarbonyl group which may be substituted, or an acyl group which may be substituted, and C 1- which may be substituted with a halogen atom.
  • a 6- alkoxycarbonyl group is more preferred.
  • R 2a is preferably a C 1-6 alkyl group which may be substituted or a C 2-6 alkenyl group which may be substituted, and more preferably a C 1-6 alkyl group which may be substituted with a halogen atom.
  • the method for producing the compound represented by the above formula (1) is not particularly limited, and can be carried out by appropriately combining known methods. Especially, it is preferable that the compound represented by Formula (1) is manufactured from the method mentioned later which uses quinic acid as a starting material at the point which is excellent in productivity.
  • the suitable aspect of the manufacturing method of the compound represented by Formula (1) is explained in full detail.
  • R 1 represents a hydrogen atom or a hydroxyl protecting group
  • R 2 represents a hydrogen atom or a carboxyl protecting group (provided that at least one of R 1 and R 2 is not a hydrogen atom)
  • R 3 to R 5 are all hydrogen atoms
  • the compound represented by the formula (1) is preferably produced by the following scheme. If it is the following method, the compound represented by Formula (1) can be manufactured efficiently. However, when R 1 is a hydrogen atom, (1a) can be produced by directly reacting (A5) with the following (A1). This method is suitable as a method for efficiently producing a compound in which R 1 is a hydroxyl protecting group and R 2 is a carboxyl protecting group.
  • L 1 represents a leaving group.
  • the compound represented by formula (A2) can be produced by reacting quinic acid represented by formula (A1) with acetone in the presence of an acid.
  • This reaction may be performed according to the method described in Rohloff J. C. et al., J. Org. Chem., 63, 4545-4550, 1998.
  • the production conditions for this reaction are not particularly limited, but the reaction temperature is preferably 20 to 60 ° C., more preferably 30 to 60 ° C., and the reaction time is preferably 1 to 6 hours, from the viewpoint that the reaction proceeds efficiently. 5 hours is more preferable.
  • finish of reaction you may add and neutralize as needed and may implement the isolation
  • the compound represented by the formula (A3) can be produced by reacting the compound represented by the formula (A2) with the compound represented by the formula (A4). As the procedure of this reaction, it can be carried out according to the procedure described in the step (A1) described above. For example, in the presence of a base (preferably, tetramethylethylenediamine), a compound represented by the formula (A2) is reacted with an alkyl chloroformate represented by R 1 -L 1 and represented by the formula (A3). There is a method for obtaining a compound.
  • a base preferably, tetramethylethylenediamine
  • the compound represented by the formula (1a) can be produced by reacting the compound represented by the formula (A3) with the compound represented by the formula (A5) in the presence of an acid catalyst.
  • the kind of the acid used is not particularly limited, and examples thereof include sulfuric acid, methanesulfonic acid, and toluenesulfonic acid, and sulfuric acid and methanesulfonic acid are preferable from the viewpoint that the reaction proceeds more efficiently at a low cost.
  • the amount of the acid used is not particularly limited, but is preferably 0.001 to 0.1 moles compared to the compound represented by the formula (A3) from the viewpoint that the reaction proceeds more efficiently, 0.005 to 0.05 times mole is more preferable.
  • R 2 in the compound represented by the formula (A5) is as described above.
  • methanol is preferable as R 2 OH in that this reaction proceeds efficiently and subsequent deprotection is easy.
  • the amount of the compound represented by the formula (A5) is not particularly limited, but is preferably 10 to 200-fold mol with respect to the compound represented by the formula (A3) from the viewpoint that the reaction proceeds more efficiently. More preferably, it is ⁇ 100 times mole.
  • a solvent may be used as necessary.
  • a compound represented by the formula (A5) is also used as a solvent.
  • the production conditions for this reaction are not particularly limited, but the reaction temperature is preferably 0 to 50 ° C., more preferably 0 to 30 ° C., and the reaction time is 1 to 1 in that the reaction proceeds efficiently and side reactions are suppressed. 8 hours are preferable, and 1 to 5 hours are more preferable.
  • the compound represented by the formula (1a) for example, in the presence of a base, the compound represented by the formula (A3) and the compound represented by the formula (A5) are reacted. Then, the method of obtaining the compound represented by Formula (1a) by making the obtained product contact with an acid is mentioned. In this method, the compound represented by the formula (1a) is synthesized by two-step treatment, and the yield is higher.
  • a base an inorganic base, a metal alkoxide, and an organic base are mentioned suitably, Sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodium ethoxide and sodium methoxide are preferable, and sodium hydrogencarbonate and sodium methoxide are more preferable. .
  • the acid examples include sulfonic acids such as sulfuric acid, methanesulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid and trifluoroacetic acid; hydrogen chloride (HCl) and the like, and sulfuric acid, methanesulfonic acid and chloride. Hydrogen is preferred, and sulfuric acid and hydrogen chloride are more preferred.
  • R 1 represents a hydrogen atom or a hydroxyl protecting group
  • R 2 represents a hydrogen atom or a carboxyl protecting group (provided that at least one of R 1 and R 2 is not a hydrogen atom)
  • R When two of 3 to R 5 are hydrogen atoms and the remainder is a group represented by the formula (3), the compound represented by the formula (1) is preferably produced by the following scheme. If it is the following method, the compound represented by Formula (1) can be manufactured efficiently.
  • the compound represented by the formula (B1) can be produced by reacting the compound represented by the formula (A3) with the compound represented by the formula (A5). This reaction is described in J. Am. Org. Chem. 71, 5397, 2006. As this reaction, for example, a compound represented by the formula (B1) is reacted with a compound represented by the formula (A3) and a compound represented by the formula (A5) under basic conditions. Can be manufactured.
  • the kind of base used for making it into basic conditions is not restrict
  • reaction conditions for this reaction are not particularly limited, but the reaction temperature is preferably 10 to 80 ° C., more preferably 20 to 50 ° C., and the reaction time is preferably 30 minutes to 5 hours, from the viewpoint that the reaction proceeds efficiently. More preferably, min-3 hours.
  • the compound represented by the formula (B2) can be produced by reacting the compound represented by the formula (B1) with the compound represented by the formula (4).
  • the procedure of this reaction may be performed according to the procedure of the step (A1) described above.
  • the compound represented by the formula (1b) can be produced by deprotecting the compound represented by the formula (B2). This reaction is described in Protective Groups in Organic Synthesis, 4th edition, pages 16-366, 2007, John Wiley & Sons, INC. May be performed according to the method described in.
  • a preferable deprotection method includes a method of reacting the compound represented by the formula (B2) with water under acidic conditions.
  • the kind of acid used for making it into acidic conditions is not restrict
  • the reaction conditions for this reaction are not particularly limited, but the reaction temperature is preferably 0 ° C. to 80 ° C., more preferably 10 ° C. to 60 ° C., and the reaction time is preferably 10 minutes to 8 hours from the viewpoint that the reaction proceeds efficiently. 30 minutes to 5 hours is more preferable.
  • R 1 represents a hydrogen atom or a hydroxyl protecting group
  • R 2 represents a hydrogen atom or a carboxyl protecting group (provided that at least one of R 1 and R 2 is not a hydrogen atom)
  • R When one of 3 to R 5 is a hydrogen atom and the remainder is a group represented by the formula (3), the compound represented by the formula (1) is preferably produced by the following scheme. If it is the following method, the compound represented by Formula (1) can be manufactured efficiently.
  • the compound represented by the formula (C1) can be produced by deprotecting the compound represented by the formula (A3). This reaction is described in Protective Groups in Organic Synthesis, 4th edition, pages 16-366, 2007, John Wiley & Sons, INC. May be performed according to the method described in.
  • a method of reacting the compound represented by the formula (A3) with an acidic aqueous solution can be mentioned.
  • the kind of acid used in the acidic aqueous solution is not particularly limited, and examples thereof include acetic acid, hydrochloric acid, and trifluoroacetic acid.
  • reaction conditions for this reaction are not particularly limited, but the reaction temperature is preferably 10 to 60 ° C., more preferably 20 to 50 ° C., and the reaction time is preferably 30 minutes to 8 hours, from the viewpoint that the reaction proceeds efficiently. ⁇ 5 hours is more preferred.
  • the compound represented by the formula (C2) can be produced by reacting the compound represented by the formula (C1) with the compound represented by the formula (4).
  • the procedure of this reaction may be performed according to the procedure of the step (A1) described above.
  • the compound represented by the formula (1c) can be produced by reacting the compound represented by the formula (C2) with the compound represented by the formula (A5).
  • the procedure of this reaction is represented by the compound represented by the formula (A3) and the formula (A5) described in [Preferred embodiment of the method for producing the compound represented by formula (1) (Part 2)].
  • the method of making it react with a compound is mentioned.
  • the compound represented by the formula (1d) can be produced by reacting the compound represented by the formula (A1) with the compound represented by the formula (A6).
  • Definition of R a in the compound represented by the formula (A6) are as described above. Of these, R a is preferably a phenyl group in that this reaction proceeds more efficiently.
  • the amount of the compound represented by the formula (A6) is not particularly limited, but is 0.95 to 1.05 moles compared to the compound represented by the formula (A1) in that the reaction proceeds more efficiently. Is preferred, and 1.0 to 1.03 moles are more preferred.
  • This reaction may be carried out in the presence of a dehydrating agent such as anhydrous sodium sulfate and molecular sieve, if necessary.
  • a dehydrating agent such as anhydrous sodium sulfate and molecular sieve
  • a solvent may be used as necessary.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include aliphatic hydrocarbons, halogenated hydrocarbons, ethers, ketones and esters. You may mix and use a solvent.
  • Preferred solvents include ethyl acetate, toluene and tetrahydrofuran.
  • the amount of the solvent to be used is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 1 to 20 times (v / w) based on the compound represented by formula (A6).
  • the compound represented by the formula (1) is preferably produced by the following scheme. If it is the following method, the compound represented by Formula (1) can be manufactured efficiently.
  • the compound represented by the formula (E1) can be produced by reacting the compound represented by the formula (1d) with the compound represented by the formula (A7).
  • R C represents a halogenated alkyl group, and examples thereof include a trifluoromethyl group, a trichloromethyl group, and a monochloromethyl group.
  • This reaction may be performed in the presence of a base, if necessary. Due to the presence of the base, the reaction proceeds more efficiently and the yield is improved. Examples of the base to be used include the bases described in the method M1 described above. Moreover, in this reaction, you may use a solvent as needed.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include the solvents described in the above-described method M1.
  • a so-called acid anhydride is used as the compound represented by the formula (A7).
  • a compound represented by the formula (8): R c COX 2 may be used.
  • X 2 represents a halogen atom.
  • the compound represented by the formula (E2) can be produced by protecting at least one of a hydroxyl group and a carboxyl group in the compound represented by the formula (E1).
  • the method of protection is not particularly limited.
  • a method of reacting a chloroformate such as methyl chloroformate, ethyl chloroformate and trichloroethyl chloroformate (ClCOOR d ) with a compound represented by the formula (E1) is there.
  • R d represents an alkyl group which may be substituted with a halogen atom.
  • R 1 in the formula (E2) represents —COOR d and R 2 represents —R d .
  • the reaction conditions in the case of using chloroformates and the like are not particularly limited, but the reaction temperature is preferably ⁇ 10 to 20 ° C., more preferably ⁇ 5 to 10 ° C., and the reaction time is from the point that the reaction proceeds efficiently. 30 minutes to 4 hours are preferable, and 1 to 3 hours are more preferable.
  • the method described in the above-mentioned [Preferred embodiment of the method for producing a compound represented by formula (1) (Part 1)] can be mentioned.
  • the compound represented by the formula (1a) can be produced by deprotecting the compound represented by the formula (E2). This reaction is described, for example, in Protective Groups in Organic Synthesis 4th edition, pages 16-366, 2007, John Wiley & Sons, INC. .)).
  • a preferable deprotection method includes a method of reacting the compound represented by the formula (E2) with water in the presence of a base. The type of base is as described above.
  • the method for producing the compound represented by the above formula (4) is not particularly limited, and can be carried out by appropriately combining known methods. Especially, it is preferable that the compound represented by Formula (4) is manufactured with the following schemes at the point which is excellent in productivity.
  • the compound represented by the formula (F2) can be produced by protecting the compound represented by the formula (F1). This reaction is described, for example, in W.W. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 370-424, 2007, John Wiley & Sons, INC.). For example, a method of reacting a compound represented by the formula (F1) with an alkyl chloroformate in the presence of a base can be mentioned.
  • the compound represented by the formula (F3) can be produced by reacting the compound represented by the formula (F2) with a halogenating agent such as thionyl chloride, thionyl bromide, phosphorus oxychloride or oxalyl chloride. .
  • a halogenating agent such as thionyl chloride, thionyl bromide, phosphorus oxychloride or oxalyl chloride.
  • This reaction may be performed according to the above-described method M2.
  • the reaction liquid is cooled after reacting the compound represented by Formula (F2) with a halogenating agent, and the compound represented by Formula (F3) There is a method of precipitating and recovering.
  • the reaction with the compound represented by Formula (1) or the compound represented by Formula (2) proceeds more efficiently.
  • the compound represented by the formula (F3) thus precipitated may be washed with a solvent to increase the purity as necessary.
  • the second embodiment of the production method of the present invention is a step of producing a compound represented by the formula (5-2) by reacting a compound represented by the formula (2) with a compound represented by the formula (4). (B1) and a step (B2) of producing the 3,4,5-tricaffeoylquinic acid by deprotecting the product obtained in the step (B1).
  • a step of producing a compound represented by the formula (5-2) by reacting a compound represented by the formula (2) with a compound represented by the formula (4).
  • Step (B1) In the step (B1), as shown in the following scheme, the compound represented by the formula (2) and the compound represented by the formula (4) are reacted to produce the compound represented by the formula (5-2). It is a process. First, the compound used at this process is explained in full detail.
  • R 3 to R 5 the definitions of R 3 to R 5 are as described above.
  • Y represents * 1 -OR b .
  • R b does not exist or represents a hydrogen atom.
  • Y represents —O—, one bond is bonded to a carbon atom represented by C1, and the other bond is bonded to M described later.
  • * 1 shows the coupling
  • the carbon atom shown by C1 intends the carbon atom shown by the white arrow in the said scheme.
  • M represents a boron atom, a silicon atom, a divalent metal ion, or a trivalent metal ion.
  • the divalent metal ion include calcium ion, magnesium ion, zinc ion, iron ion, cobalt ion, chromium ion, copper ion and nickel ion.
  • trivalent metal ions include iron ions and aluminum ions. Among these, a boron atom, a calcium ion, a magnesium ion, and a zinc ion are preferable, and a boron atom and a zinc ion are more preferable in that the compound represented by the formula (2) has excellent synthesis suitability and the reaction proceeds more efficiently. .
  • A is absent or represents a monovalent cation.
  • monovalent cations include alkali metal ions. Of these, potassium ion and sodium ion are preferred because they are excellent in synthesis suitability for the compound represented by formula (2) and are easily isolated.
  • n represents an integer of 2 or 3. Note that m varies depending on the type of M. In the first embodiment, when M is a boron atom, m is 2 and A is a monovalent cation. As a second embodiment, when M is a silicon atom, m represents 2 and A does not exist. As a third aspect, when M is a divalent metal ion, m represents 2 and A does not exist. As a fourth aspect, when M is a trivalent metal ion, m represents 3 and A does not exist. About each aspect, it shows with a structural formula below. Hereinafter, the compound represented by formula (2-1) is the first embodiment, the compound represented by formula (2-2) is the second embodiment, and the compound represented by formula (2-3) is the third. The compound represented by the formula (2-4) corresponds to the fourth aspect.
  • Step (B2) In the step (B2), as shown in the following scheme, the product (compound represented by the formula (5-2)) obtained in the step (B1) is deprotected, and 3,4,5-tricaffeoyl It is a process for producing quinic acid. More specifically, a protecting group (such as a phenolic hydroxyl protecting group) contained in the compound represented by the above formula (5-2) is eliminated to obtain a desired 3,4,5-tricaffeoylquinic acid. It is the process of obtaining. In this step, deprotection is intended to remove the group protecting the hydroxyl group, phenolic hydroxyl group and carboxyl group in 3,4,5-tricaffeoylquinic acid as described above. . Accordingly, deprotection also includes detaching the portion represented by M.
  • a protecting group such as a phenolic hydroxyl protecting group contained in the compound represented by the above formula (5-2) is eliminated to obtain a desired 3,4,5-tricaffeoylquinic acid. It is the process of obtaining.
  • the compound represented by the formula (6) can be produced by deprotecting the compound represented by the formula (5-2). This reaction is described, for example, in Protective Groups in Organic Synthesis 4th edition, pages 367-430, 2007, John Wiley & Sons, INC. .)). This reaction may be performed according to the method described in the above step (A2).
  • a compound represented by the formula (5-3) is produced from a compound represented by the formula (5-2). And a method for producing a compound represented by formula (6) by deprotecting the compound represented by -3). According to the following scheme, the compound represented by formula (6) can be more efficiently produced.
  • the method for producing the compound represented by the formula (5-3) from the compound represented by the formula (5-2) is not particularly limited, but the compound represented by the formula (5-3) can be efficiently obtained. And a method of bringing the compound represented by the formula (5-2) into contact with an acidic aqueous solution or an aqueous chelating agent solution.
  • an acidic aqueous solution or an aqueous chelating agent solution.
  • acidic aqueous solution is not restrict
  • the chelating agent contained in the chelating agent aqueous solution include EDTA and PDTA.
  • the temperatures of the acidic aqueous solution and the chelating agent aqueous solution are not particularly limited, but are preferably 0 ° C. to 40 ° C., more preferably 10 ° C. to 30 ° C., in that the reaction proceeds more efficiently.
  • the reaction time of the compound represented by the formula (5-2) and the acidic aqueous solution or chelating agent aqueous solution is not particularly limited, but is preferably 1 minute to 1 hour from the viewpoint of the yield and productivity of the product, 3 minutes More preferred is 30 minutes.
  • the compound represented by the formula (6) can be produced by deprotecting the compound represented by the formula (5-3). This reaction is described, for example, in Protective Groups in Organic Synthesis 4th edition, pages 367-430, 2007, John Wiley & Sons, INC. .)). This reaction may be performed according to the method described in the above step (A2).
  • the production method of the compound represented by the above formula (2) is not particularly limited, and can be carried out by appropriately combining known methods. Especially, it is preferable that the compound represented by Formula (2) is manufactured from the method which uses quinic acid as a starting material at the point which is excellent in productivity.
  • a method for producing the compound represented by the above formula (2-1) includes a method in which quinic acid and boric acid are reacted in the presence of a base. At that time, a cation is present as Z, and the type of cation depends on the type of base used.
  • the reaction solution was poured into 1 L of cold dilute hydrochloric acid, 300 mL of ethyl acetate was added, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane / isopropanol to obtain 18.5 g of white crystals of 1-carbomethoxy-3,4-O-isopropylidene-1,5-quinidelactone. 5 drops of methanesulfonic acid was added to a mixture of 5.44 g of the obtained white crystals and 200 mL of methanol, and the mixture was heated and stirred at 60 ° C.
  • the inorganic substance was filtered off, and the inorganic substance was washed with methanol.
  • the filtrate and the washing solution were combined, the solvent was distilled off under reduced pressure, 8.7 g of anhydrous lithium bromide and 40 mL of pyridine were added to the residue, and the mixture was heated to reflux for 4 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain 0.7 g of 3,4,5-tricaffeoylquinic acid (TCQA).
  • TCQA 3,4,5-tricaffeoylquinic acid
  • the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane), and 0.7 g of methyl 1-carbomethoxy-3,4,5-tris (3,4-dicarbomethoxycaffeoyl) quinate Got.
  • the residue was analyzed by 1 H-NMR, and as a result, the purity of methyl 1-carbomethoxy-3,4,5-tris (3,4-diacetylcaffeoyl) quinate contained in the residue was 92% by weight. The rate was 98%.
  • the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain 34.7 g of methyl 1-carbomethoxy-3,4,5-tris (3,4-diacetylcaffeoyl) quinate. It was. 10.46 g of lithium hydroxide at 10 to 20 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne : un procédé de fabrication d'acide 3,4,5-tricaféoylquinique de manière efficace, en utilisant des matières premières bon marché à travers des étapes courtes et des fonctionnements pratiques; et un composé intermédiaire. Ce procédé de fabrication d'un acide 3,4,5-3,4,5-tricaféoylquinique comprend au moins une étape (1) de réaction d'un composé représenté par la formule (1) ou d'un composé représenté par la formule (2) avec un composé représenté par la formule (4), et une étape (2) de déprotection du produit obtenu à l'étape (1) et de fabrication de l'acide 3,4,5-3,4,5-tricaféoylquinique.
PCT/JP2014/060176 2013-04-08 2014-04-08 Procédé de fabrication d'acide 3,4,5-tricaféoylquinique WO2014168139A1 (fr)

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DE112014001871.6T DE112014001871B4 (de) 2013-04-08 2014-04-08 Verfahren zur Herstellung von 3,4,5-Tricaffeoylchinasäure
JP2015511264A JP6139667B2 (ja) 2013-04-08 2014-04-08 ３，４，５−トリカフェオイルキナ酸の製造方法
CN201480020134.8A CN105143171B (zh) 2013-04-08 2014-04-08 3,4,5-三咖啡酰奎尼酸的制造方法
US14/876,931 US9475752B2 (en) 2013-04-08 2015-10-07 Method for manufacturing 3,4,5-tricaffeoylquinic acid

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JP2005298382A (ja) * 2004-04-09 2005-10-27 National Agriculture & Bio-Oriented Research Organization ３，４，５−トリ−ｏ−カフェオイルキナ酸の製造方法
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MIYAMAE, Y. ET AL.: "Structure-Activity Relationship of Caffeoylquinic Acids on the Accelerating Activity on ATP Production", CHEM. PHARM. BULL., vol. 59, no. 4, 2011, pages 502 - 507 *
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US20160023986A1 (en) 2016-01-28
DE112014001871T5 (de) 2015-12-31
CN105143171B (zh) 2018-07-10
DE112014001871B4 (de) 2019-11-14
US9475752B2 (en) 2016-10-25
JPWO2014168139A1 (ja) 2017-02-16
JP6139667B2 (ja) 2017-05-31

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